Targeting Protein Tyrosine Phosphatases via PROteolysis-TArgeting Chimeras (PROTACs): Current Developments and Prospects

Abstract

Protein tyrosine phosphatases (PTPs) are prominent enzymes which play pivotal roles in the regulation of multifarious cellular functions. Dysregulations of several PTPs have well-documented implications in the pathogenesis of various human diseases, including diabetes, cancer, and neurodegenerative and inflammatory disorders. Therefore, PTPs are considered attractive targets for therapeutic intervention. However, the development of novel drugs targeting these enzymes has encountered several difficulties. Currently, it has become clear that improving PTP druggability can be an attainable goal, through different medicinal chemistry approaches. Besides the development of allosteric inhibitors of PTPs, the design of PROteolysis-TArgeting Chimeras (PROTACs) has emerged as a promising strategy capable of providing a useful alternative mechanism to control these enzymes through their targeted degradation. Although the development of PROTACs directed to PTPs is still in its infancy, the results so far available are promising; this perspective study focuses on this class of potential novel drugs, highlighting advantages and challenging aspects to consider for future progress.